title: Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 gene that result in a deficiency of SMN protein. One approach to treat SMA is to use antisense oligonucleotides (ASOs) to redirect the splicing of a paralogous gene, SMN2, to boost production of functional SMN. Injection of a 2'-O-2-methoxyethyl-modified ASO (ASO-10-27) into the cerebral lateral ventricles of mice with a severe form of SMA resulted in splice-mediated increases in SMN protein and in the number of motor neurons in the spinal cord, which led to improvements in muscle physiology, motor function and survival. Intrathecal infusion of ASO-10-27 into cynomolgus monkeys delivered putative therapeutic levels of the oligonucleotide to all regions of the spinal cord. These data demonstrate that central nervous system-directed ASO therapy is efficacious and that intrathecal infusion may represent a practical route for delivering this therapeutic in the clinic.
authors.affiliation: Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701, USA. marco.passini@genzyme.com
authors.forename: Marco A
authors.initials: MA
authors.lastname: Passini
authors.forename: Jie
authors.initials: J
authors.lastname: Bu
authors.forename: Amy M
authors.initials: AM
authors.lastname: Richards
authors.forename: Cathrine
authors.initials: C
authors.lastname: Kinnecom
authors.forename: S Pablo
authors.initials: SP
authors.lastname: Sardi
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Stanek
authors.forename: Yimin
authors.initials: Y
authors.lastname: Hua
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.forename: John
authors.initials: J
authors.lastname: Matson
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.forename: Edward M
authors.initials: EM
authors.lastname: Kaye
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D009046:Motor Neurons / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D009469:Neuromuscular Junction / Q000648:ultrastructure; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012326:RNA Splicing; D013116:Spinal Cord / Q000473:pathology* / Q000503:physiopathology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: D016376:Oligonucleotides, Antisense; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein